Lecture 6 - Haemostasis Flashcards
(22 cards)
Haemostasis is a coordinated response from 3 components, what are these?
Haemostasis is caused by vessel constriction, platelet activation and coagulation.
Haemostasis is a rapid localised process, but what factors can cause increased bleeding or thrombosis?
Increased bleeding or thrombosis can occur due to there being vessel wall damage, abnormal numbers or functions of platelets, or reduced or abnormal coagulation proteins or their inhibitors.
A low concentraion of platelets increases the risk of bleeding. What is bleeding into the skin due to reduced platelet count called?
Purpura. Large purpura are called ecchymoses, whilst small pinpoint sites of bleeding from capillaries are called petechiae.
What are the 5 requirements for normal haemostasis?
Normal vessel walls
Normal endothelium
Normal amounts of functionally normal coagulation factors
Normal blood flow and normal inhibitors of coagulation and platelet activation
Describe the features of a platelet (both morphology, and contents)
Platelets are a flattened disk shape which is maintained by coiled microtubules. On the surface are receptors (GPla, GPlb) (GpIIb and GPIIIa are fibrinogen receptors), which when bound to a specific molecule activate the platelet. Inside are granules, which come as either alpha or dense granules. There is also a canalicular sysytem which opens it to the outside environment. Also, it contains mitochondria and glycogen for energy.
The first step of the platelet response to vascular damage is platelet adhesion, how does this occur?
In the platelet membrane are receptor glycoproteins GPla and GPlb.GPla binds to collagen in the basement membrane and tissues.GPlb binds to von Willebrand factor (vWF), which is produced by endothelial cells for adhesion. vWF is secreted both under the endothelial cell for adhesion to basement membrane, and into the plasma.
What are the 4 steps of platelet activation?
- Shape change - sphere & pseudopods form
- Granules are secreted - into canalicular system which empties to outside environment (inside granules are ADP, serotonin, vWF, Anti heparin)
- Phospholipase system is activated, where arachadonic acid is removed from membranes within the cell to enter the COX pathway to produce Thromboxane A2, which is a potent activator of platlets.
- GPllb & Gplla become activated once they bind to fibrinogen or vWF, this causes the platelets to aggregate
Platelet activation is initially reversible, as platelet activation and aggregation depends on what?
Platelet activation depends on strength of activation stimuli. A weak stimuli will result in a partial release reaction and reversible aggregration. Reversible platelet activation can also occur when there is shearing stress from turbulent blood flow. e.g. hypertension, atherosclerosis, branching of arteries.
During the release reaction platelets secrete dense and alpha granules. What are inside each type of granule?
Dense granules contain Calcium, ADP, Serotonin (causes vasoconstriction and platelet activation)
Alpha granules contain Fibrinogen, vWF, Factor V, Factor Vlll Platelet specific: platelet factor 4 (an anti-heparin) beta - Thromboglobulin, and a variety of mediators of inflammation and tissue repair
What is the general sequence of events for the response of platelets to a damaged vessel wall?
Adhesion
Activation
Release reaction
More platelets induced to aggregate Platelets provide phospholipid (Platelet factor 3 - needed to support coagulation)
Clot retraction - contraction of platelet actin-myosin, takes ~1hr
Why is the platelet plug essential for stopping bleeding?
The platelet plug activates coagulation factors that are not washed away, and it’s required for activation of coagulation
What are the basics for the PFA-100 test? (Platelet function Analyser)
A capillary coated with activators has blood drawn through it, and time it takes for capillary occulsion by a platelet plug is measured.
Where do platelets come from?
Platelets bud off from megakaryocytes in bone marrow
What is the reference range for platelets? And what is the range for mild, moderate and severe thrombocytopenia?
Reference range: 150-400x10e9 Mild: 50-150e9/L Slow oozing from all cut surfaces Moderate: 20-50e9/L Bruising common Severe: <20e9/L Brusing with minimal traumaCan be life threatening bleeding into brain, or gut
What are four processes that can cause thrombocytopaenia? (Low platelet count)
Reduced production - can be hereditary, or acquired(most common)
Shorterned survival - can be caused by consumption of platelets by coagulation
Dilutional - platelets can be lowered after massive transfusion
Sequestration into the spleen (30-80% of platelets can sequester in abnormally large spleen)
What things cause a reduced production of platelets?
Global marrow depression e.g. Chemotherapy, radiotherapy Marrow failure due to marrow replacement - Cancer of bone marrow cells (leukaemia, plasma cell myeloma), or secondary marrow infiltration (cancer, fibrosis etc)
Selective depression of megakaryocytes - caused by some viral infections (chicken pox), and by many drugs and chemicals
Aplastic anaemia
Also by Hereditary
What can cause shortened survival of platelets?
Increased platelet destuction, which can be autoimmune, like in immune thrombocytopenia (autoantibody binds to platelets - cleared by spleen), or CD8+ cells can destroy platelets. Drugs can form an immune complex of plasma protein + drug + antibody, and this binds to platelet and can clear in spleen. Platelets can have their survival shortened also due to activation, where they are consumed. Circulating immune complexes can activate platelets. Also lowered by disseminated intravascular coagulation. Can be caused by gram negative septicaemia, which activates platelets with its endotoxin.
What are some anti-platelet drugs ?
Aspirin - Cyclooxygenase inhibitor, where TXA2 synthesis is blocked, which results in reduced platelet activation, resulting in a smaller, slower forming platelet plug.
Clopidogrel - ADP receptor blocker
GPllb-GPlla inhibitors - which can be things such as fibrin, collagen analogues
NSAIDS - Non-steroidal anti-inflammatory drugs (but not paracetamol, opiates and tramadol)
What are some inheritable severe defects which affect haemostasis?
What do endothelial cells secrete to prevent coaguation in normal blood flow? And what are some general features that prevent platelet activation in normal blood flow?
In normal blood flow platelets are normally unable to adhere to endothelium. This is because endothelial cells are secreting Nitric oxide (NO), and prostacylcin (PGI2). These dilate blood vessels, and inhibit platelet activation.The velcotiy of blood flow is faster in the centre of the vessel, and this results in there being less shearing force against the endothelium, which results in less activation. The central zone is red-cell rich, whilst the peripheries are plasma and platelet-rich.Also, endothelial cells clear ADP secreted by activated platelets.
When endothelial cells become activated to enter a procoagulant state, what protein is expressed, and what peptide is secreted?
P-selectin is expressed on the endothelial surface to increase adhesion to platelets.Endothelin is secreted to cause vasoconstriction.
What occurs during coagulation when the endothelial cells haev been lost?
Vessel constriction - nerve relfex
Platelets adhere to connective tissue (collagen and vWF)
Platelet activation and release reaction (ADP release, release of serotonin, TXA2 synthesis)
More platelets activated and aggregated -> plug forms, bleeding from small vessels stops
